The Section is conducting patient-oriented research about the etiology, pathophysiology, genetics, diagnosis, and treatment of pheochromocytoma (PHEO) and paraganglioma (PGL). Projects include not only translational research-applying basic science knowledge to clinical diagnosis, pathophysiology, and treatment-but also reverse translation research where appreciation of clinical findings leads to new concepts that basic researchers can pursue in the laboratory. In order to achieve our goals, the strategy of the Section is based on the multidisciplinary collaborations among NIH investigators and outside medical centers. Our Section links together a patient-oriented component with two bench-level components. The patient-oriented component (Medical Neuroendocrinology) is currently the main driving force for our hypotheses and discoveries. The two bench-level components (Tumor Pathogenesis and Chemistry & Biomarkers) emphasize first, technologies of basic research tailored for pathway and target discovery and second, the development of the discoveries into clinical applications. Hereditary PHEO/PGL Previously, we reported a new syndrome, characterized by tumor-specific gain-of-function mutations in hypoxia-inducible factor 2 (HIF2A), leading to the development of multiple PGLs and duodenal somatostatinomas associated with secondary polycythemia (Pacak-Zhuang syndrome). In another study we tested whether duodenal GPGLs share a similar pathogenic mechanism with PGLs associated with somatic HIF2A mutations. Ten GPGL tissues were screened for somatic HIF2A mutation and 2 of them were found to have HIF2A mutation. Similar to this study, we found that some CNS hemangioblastomas were found to have HIF2A mutation. The Cancer Genome Atlas (TCGA) is a comprehensive and coordinated effort to accelerate our understanding of the molecular basis of selected cancers through the application of large-scale genome analysis technologies. TCGA was funded by NCI/NIH, and we lobbied for PHEO and PGL to be included in the TCGA effort. After acceptance, we served as the major collaborative center with Dr. Pacak as co-chair. Together with other investigators, we achieved the largest and most detailed molecular catalogue of PHEOs/PGLs, which included 178 cases analyzed with whole-exome sequencing, copy-number analysis, messenger RNA sequencing, microRNA sequencing, and DNA-methylation analysis. We identified two previously unrecognized molecular alterations including the somatic MAML3 fusion gene and somatic CSDE1 gene mutations that were associated with clinically aggressive disease. Additional molecular discriminants of clinically aggressive disease included ATRX, and SETD2 mutations. We also identified 4 molecular subtypes of PHEO/PGL with distinct molecular alterations and clinical profiles: the kinase signaling subtype (HRAS, RET, and NF1 mutations), (pseudo)hypoxic subtype (SDHB, VHL, and HIF2A mutations), Wnt-altered subtype (CSDE1 mutations and MAML3 fusions), and cortical admixture subtype (MAX mutations). Sixty-nine percent of tumors had driver alterations, which were either germline or somatic mutations or a somatic gene fusion. Driver alterations were essentially mutually exclusive. Patients with clinically aggressive disease had a significantly different molecular profile in their primary tumors as compared to other patients. Although these findings are currently under journal review, the underlying data is already available for any investigator to download and process. Thus, TCGA now offers the PHEO/PGL community an invaluable resource, which may continue to fuel discoveries and ultimately lead to improved understanding of these tumors. Imaging and PHEO/PGL In our first study, 68Ga-DOTATATE PET was prospectively performed in 17 patients with SDHB-related metastatic PHEOs/PGLs45. All patients also underwent 18F-FDG PET and CT/MRI, with 16 of the 17 patients also receiving 18F-fluorodihydroxyphenylalanine (18F-FDOPA) and 18F-FDA PET scans. Detection rates of metastatic lesions were compared among all performed functional imaging studies. 68Ga-DOTATATE PET showed a detection rate of 98.6% 95% confidence interval (CI), 96.5%99.5%, 18F-FDG, 18F-FDOPA, 18F-FDA PET, and CT/MRI showed detection rates of 85.8% (CI, 81.3%89.4%; P < 0.01), 61.4% (CI, 55.6%66.9%; P < 0.01), 51.9% (CI, 46.1%57.7%; P < 0.01), and 84.8% (CI, 80.0%88.5%; P < 0.01), respectively. 68Ga-DOTATATE PET showed a significantly superior detection rate among other functional and anatomical imaging modalities. Thus, we concluded that 68Ga-DOTATATE PET may represent the preferred future imaging modality in the evaluation of SDHB-related metastatic PHEO/PGL. In our subsequent studies we found that 68Ga-DOTATATE PET is also an excellent and superior functional imaging modality to other imaging modalities in the detection of sporadic metastatic PHEO and PGL including those located in the head and neck. These results suggest that treatment using DOTA-analogs, especially 177Lu-DOTATATE can be of a huge interest in patients with metastatic PHEO/PGL. Treatment of PHEO/PGL In several studies we found that topoisomerase I inhibitors (e.g. LMP-400), NF-kappaB inhibitors (e.g. triptolide); MAPK pathway inhibitors (e.g. various statins) with or without 13-cis retinoic acid; a dual mTORC1/2 small molecular inhibitor (AZD 8055); and ATP synthase inhibitors could be potential excellent targets in treatment of metastatic PHEO/PGL. We have initiated collaboration with NCI to use hypomethylating agents in treatment of metastatic PHEO/PGL.